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Single-cell transcriptomic profiling reveals decreased ER protein Reticulon3 drives the progression of renal fibrosis. 单细胞转录组分析显示,ER 蛋白 Reticulon3 的减少推动了肾脏纤维化的进展。
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-28 DOI: 10.1186/s43556-024-00187-x
Shuai Guo, Yi Dong, Ran Du, Yu-Xing Liu, Shu Liu, Qin Wang, Ji-Shi Liu, Hui Xu, Yu-Jie Jiang, Huang Hao, Liang-Liang Fan, Rong Xiang

Chronic kidney disease (CKD) poses a significant global health dilemma, emerging from complex causes. Although our prior research has indicated that a deficiency in Reticulon-3 (RTN3) accelerates renal disease progression, a thorough examination of RTN3 on kidney function and pathology remains underexplored. To address this critical need, we generated Rtn3-null mice to study the consequences of RTN3 protein deficiency on CKD. Single-cell transcriptomic analyses were performed on 47,885 cells from the renal cortex of both healthy and Rtn3-null mice, enabling us to compare spatial architectures and expression profiles across 14 distinct cell types. Our analysis revealed that RTN3 deficiency leads to significant alterations in the spatial organization and gene expression profiles of renal cells, reflecting CKD pathology. Specifically, RTN3 deficiency was associated with Lars2 overexpression, which in turn caused mitochondrial dysfunction and increased reactive oxygen species levels. This shift induced a transition in renal epithelial cells from a functional state to a fibrogenic state, thus promoting renal fibrosis. Additionally, RTN3 deficiency was found to drive the endothelial-to-mesenchymal transition process and disrupt cell-cell communication, further exacerbating renal fibrosis. Immunohistochemistry and Western-Blot techniques were used to validate these observations, reinforcing the critical role of RTN3 in CKD pathogenesis. The deficiency of RTN3 protein in CKD leads to profound changes in cellular architecture and molecular profiles. Our work seeks to elevate the understanding of RTN3's role in CKD's narrative and position it as a promising therapeutic contender.

慢性肾脏病(CKD)是一个严重的全球性健康难题,其产生原因复杂。尽管我们之前的研究表明,网状神经元3(RTN3)的缺乏会加速肾脏疾病的进展,但对RTN3对肾脏功能和病理影响的深入研究仍然不足。为了满足这一迫切需要,我们培育了Rtn3缺失小鼠,以研究RTN3蛋白缺乏对CKD的影响。我们对来自健康小鼠和 Rtn3 缺失小鼠肾皮质的 47,885 个细胞进行了单细胞转录组分析,比较了 14 种不同细胞类型的空间结构和表达谱。我们的分析表明,RTN3 缺乏会导致肾细胞的空间组织和基因表达谱发生显著改变,从而反映出慢性肾功能衰竭的病理变化。具体来说,RTN3 缺乏与 Lars2 过度表达有关,而 Lars2 过度表达又会导致线粒体功能障碍和活性氧水平升高。这种转变诱导肾上皮细胞从功能状态转变为纤维化状态,从而促进肾纤维化。此外,研究还发现 RTN3 缺乏会推动内皮细胞向间质转化过程,并破坏细胞间的交流,从而进一步加剧肾脏纤维化。免疫组化和Western-Blot技术被用来验证这些观察结果,从而加强了RTN3在CKD发病机制中的关键作用。CKD 中 RTN3 蛋白的缺乏会导致细胞结构和分子特征发生深刻变化。我们的工作旨在提高人们对 RTN3 在 CKD 中作用的认识,并将其定位为一种有前景的治疗方法。
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引用次数: 0
Inhibition of cysteine-serine-rich nuclear protein 1 ameliorates ischemia-reperfusion injury during liver transplantation in an MAPK-dependent manner. 抑制富含半胱氨酸-丝氨酸的核蛋白 1 能以 MAPK 依赖性方式改善肝移植过程中的缺血再灌注损伤。
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-21 DOI: 10.1186/s43556-024-00185-z
Zhoucheng Wang, Wenwen Ge, Xinyang Zhong, Shizheng Tong, Shusen Zheng, Xiao Xu, Kai Wang

Hepatic ischemia-reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are dysregulated during HIRI. This study aims to identify genes as potential therapeutic targets for ameliorating HIRI. Datasets containing samples from the human donor liver (GSE151648) and mouse HIRI model (GSE117066) were analyzed to determine differentially expressed genes (DEGs). The selected DEGs were confirmed by real-time PCR and western blot in the hepatocyte hypoxia-reoxygenation (HR) model, mouse HIRI model, and human liver samples after transplantation. Genetic inhibition was used to further clarify the underlying mechanism of the gene in vitro and in vivo. Among the DEGs, CSRNP1 was significantly upregulated (|log FC|= 2.08, P < 0.001), and was positively correlated with the MAPK signal pathway (R = 0.67, P < 0.001). CSRNP1 inhibition by siRNA significantly suppressed apoptosis in the AML-12 cell line after HR (mean Annexin+ ratio = 60.62% vs 42.47%, P = 0.0019), but the protective effect was eliminated with an additional MAPK activator. Knocking down CSRNP1 gene expression by intravenous injection of AAV-shRNA markedly reduced liver injury in mouse HIRI model (ALT: AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8, P < 0.001; AST: AAV-NC vs AAV-shCsrnp1 = 8640.5 ± 1450.3 vs 1786.8 ± 518.3, P < 0.001). Liver-targeted delivery of siRNA by nanoparticles effectively inhibited intra-hepatic genetic expression of Csrnp1 and alleviated IRI by reducing tissue inflammation and hepatocyte apoptosis. Furthermore, CSRNP1 inhibition was associated with reduced activation of the MAPK pathway both in vitro and in vivo. In conclusion, our results demonstrated that CSRNP1 could be a potential therapeutic target to ameliorate HIRI in an MAPK-dependent manner.

肝脏缺血再灌注损伤(HIRI)是肝移植(LT)过程中的一个关键病理生理过程。在肝缺血再灌注损伤过程中,多种基因和信号通路失调。本研究旨在确定作为潜在治疗靶点的基因,以改善 HIRI。研究人员分析了包含人类供体肝脏样本(GSE151648)和小鼠 HIRI 模型样本(GSE117066)的数据集,以确定差异表达基因(DEGs)。在肝细胞缺氧-复氧(HR)模型、小鼠 HIRI 模型和移植后的人类肝脏样本中,通过实时 PCR 和 Western 印迹证实了所选的 DEGs。通过基因抑制进一步阐明了该基因在体外和体内的潜在机制。在 DEGs 中,CSRNP1 明显上调(|log FC|= 2.08,P + ratio = 60.62% vs 42.47%,P = 0.0019),但使用额外的 MAPK 激活剂后,保护作用被消除。在小鼠 HIRI 模型中,通过静脉注射 AAV-shRNA 敲低 CSRNP1 基因表达明显减轻了肝损伤(ALT:AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8,P||=2.08)。
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引用次数: 0
Ckip-1 3'UTR alleviates prolonged sleep deprivation induced cardiac dysfunction by activating CaMKK2/AMPK/cTNI pathway. Ckip-1 3'UTR通过激活CaMKK2/AMPK/cTNI通路缓解长期睡眠剥夺诱发的心功能障碍。
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1186/s43556-024-00186-y
Beilei Dong, Rui Xue, Jianwei Li, Shukuan Ling, Wenjuan Xing, Zizhong Liu, Xinxin Yuan, Junjie Pan, Ruikai Du, Xinming Shen, Jingwen Zhang, Youzhi Zhang, Yingxian Li, Guohui Zhong

Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function. Echocardiography analysis revealed that cardiac function was significantly decreased in mice after five weeks of SD. Real-time quantitative PCR (RT-q-PCR) and Masson staining analysis showed that cardiac remodeling marker gene Anp (atrial natriuretic peptide) and fibrosis were increased, Elisa assay of serum showed that the levels of creatine kinase (CK), creatine kinase-MB (CK-MB), ANP, brain natriuretic peptide (BNP) and cardiac troponin T (cTn-T) were increased after SD, suggesting that cardiac remodeling and injury occurred. Transcript sequencing analysis indicated that genes involved in the regulation of calcium signaling pathway, dilated cardiomyopathy, and cardiac muscle contraction were changed after SD. Accordingly, Western blotting analysis demonstrated that the cardiac-contraction associated CaMKK2/AMPK/cTNI pathway was inhibited. Since our preliminary research has confirmed the vital role of Casein Kinase-2 -Interacting Protein-1 (CKIP-1, also known as PLEKHO1) in cardiac remodeling regulation. Here, we found the levels of the 3' untranslated region of Ckip-1 (Ckip-1 3'UTR) decreased, while the coding sequence of Ckip-1 (Ckip-1 CDS) remained unchanged after SD. Significantly, adenovirus-mediated overexpression of Ckip-1 3'UTR alleviated SD-induced cardiac dysfunction and remodeling by activating CaMKK2/AMPK/cTNI pathway, which proposed the therapeutic potential of Ckip-1 3'UTR in treating SD-induced heart disease.

睡眠不足(SD)已成为影响人类健康的一个重要问题,会对心血管系统造成严重损害。然而,其潜在机制尚不清楚,靶向药物的开发也相对滞后。在这里,我们用小鼠来探讨长期SD对心脏结构和功能的影响。超声心动图分析表明,小鼠在SD五周后心脏功能明显下降。实时定量 PCR(RT-q-PCR)和 Masson 染色分析表明,心脏重塑标志基因 Anp(心房利钠肽)和纤维化增加、血清中肌酸激酶(CK)、肌酸激酶-MB(CK-MB)、ANP、脑钠肽(BNP)和心肌肌钙蛋白 T(cTn-T)的水平在 SD 后升高,表明心脏发生了重塑和损伤。转录本测序分析表明,参与钙信号通路调控、扩张型心肌病和心肌收缩的基因在 SD 后发生了变化。相应地,Western 印迹分析表明,与心肌收缩相关的 CaMKK2/AMPK/cTNI 通路受到了抑制。我们的初步研究证实了酪蛋白激酶-2-互作蛋白-1(CKIP-1,又称 PLEKHO1)在心脏重塑调控中的重要作用。在此,我们发现SD后Ckip-1的3'非翻译区(Ckip-1 3'UTR)水平下降,而Ckip-1的编码序列(Ckip-1 CDS)保持不变。值得注意的是,腺病毒介导的Ckip-1 3'UTR过表达通过激活CaMKK2/AMPK/cTNI通路缓解了SD诱导的心功能障碍和重塑,这提出了Ckip-1 3'UTR在治疗SD诱导的心脏病方面的治疗潜力。
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引用次数: 0
Signaling pathways in colorectal cancer implications for the target therapies. 结直肠癌信号通路对靶向疗法的影响。
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-07 DOI: 10.1186/s43556-024-00178-y
Yanlin Song, Ming Chen, Yuhao Wei, Xuelei Ma, Huashan Shi

Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.

结直肠癌(CRC)是一个紧迫的全球性健康问题,其特点是未成熟细胞在多方面内外因素的影响下肆意增殖。大量研究探索了 CRC 肿瘤发生的复杂机制,主要重点是信号通路,尤其是与生长因子和趋化因子相关的信号通路。然而,分子靶点的多样性给靶向疗法的选择带来了复杂性,给实现精准治疗带来了巨大挑战。由于缺乏对肿瘤细胞突变或改变的病理学洞察,寻找有效的 CRC 治疗方法变得更加复杂。这项研究揭示了从细胞膜到细胞核的信号传递,揭示了这一关键细胞过程的最新进展。通过揭示这一新颖的层面,研究加深了我们对 CRC 潜在的分子复杂性的理解,为靶向治疗策略的突破提供了潜在的途径。此外,该研究还全面概述了信号通路异常激活所引发的潜在免疫反应,重点关注免疫细胞、细胞因子及其对药物开发动态格局的集体影响。这项研究不仅极大地推动了结直肠癌治疗和分子医学的发展,还为未来的突破和临床试验奠定了基础,为改善结直肠癌的治疗效果和改进治疗方法带来了希望。
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引用次数: 0
Signaling pathways in liver cancer: pathogenesis and targeted therapy. 肝癌的信号通路:发病机制和靶向治疗。
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-31 DOI: 10.1186/s43556-024-00184-0
Yangtao Xue, Yeling Ruan, Yali Wang, Peng Xiao, Junjie Xu

Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.

肝癌是全球最常见的恶性肿瘤之一,发病率和死亡率都很高。由于起病隐匿,肝癌通常在晚期才被确诊,此时手术治疗已不再可行。这种情况凸显了系统治疗(包括靶向治疗)在改善患者预后方面的关键作用。尽管对肝癌的发病机制进行了大量研究,但酪氨酸激酶抑制剂(TKIs)是目前唯一广泛应用于临床的抑制剂,以索拉非尼为代表,其临床应用受到耐药现象的极大限制。在此,我们将深入探讨肝癌发病机制中经常涉及的信号通路,以及针对这些通路正在研究或已用于晚期肝癌治疗的抑制剂。我们分别阐明了这些通路在肝癌尤其是肝细胞癌(HCC)中的致癌作用以及抑制剂的研究现状。鉴于TKIs是目前临床上唯一的肝癌靶向治疗药物,我们特别关注TKIs及其在HCC治疗中常见的耐药现象的机制。这就要求我们必须开发创新的靶向策略,克服现有的局限性。本综述旨在阐明晚期肝癌靶向治疗的应用,以期改善这些患者不尽人意的预后前景。
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引用次数: 0
Carcinoembryonic antigen potentiates non-small cell lung cancer progression via PKA-PGC-1ɑ axis. 癌胚抗原通过 PKA-PGC-1ɑ 轴促进非小细胞肺癌的进展
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-24 DOI: 10.1186/s43556-024-00181-3
Juan Lei, Lei Wu, Nan Zhang, Xudong Liu, Jiangang Zhang, Liwen Kuang, Jiongming Chen, Yijiao Chen, Dairong Li, Yongsheng Li

Carcinoembryonic antigen (CEA) is a tumor-associated antigen primarily produced by tumor cells. It has been implicated in various biological processes such as cell adhesion, proliferation, differentiation, and metastasis. Despite this, the precise molecular mechanisms through which CEA enhances tumor cell proliferation remain largely unclear. Our study demonstrates that CEA enhances the proliferation and migration of non-small cell lung cancer (NSCLC) while also inhibiting cisplatin-induced apoptosis in NSCLC cells. Treatment with CEA led to an increase in mitochondrial numbers and accumulation of lipid droplets in A549 and H1299 cells. Additionally, our findings indicate that CEA plays a role in regulating the fatty acid metabolism of NSCLC cells. Inhibiting fatty acid metabolism significantly reduced the CEA-mediated proliferation and migration of NSCLC cells. CEA influences fatty acid metabolism and the proliferation of NSCLC cells by activating the PGC-1α signaling pathway. This regulatory mechanism involves CEA increasing intracellular cAMP levels, which in turn activates PKA and upregulates PGC-1α. In NSCLC, inhibiting the PKA-PGC-1α signaling pathway reduces both fatty acid metabolism and the proliferation and migration induced by CEA, both in vitro and in vivo. These results suggest that CEA contributes to the promotion of proliferation and migration by modulating fatty acid metabolism. Targeting CEA or the PKA-PGC-1ɑ signaling pathway may offer a promising therapeutic approach for treating NSCLC.

癌胚抗原(CEA)是一种肿瘤相关抗原,主要由肿瘤细胞产生。它与细胞粘附、增殖、分化和转移等多种生物过程有关。尽管如此,CEA 增强肿瘤细胞增殖的确切分子机制在很大程度上仍不清楚。我们的研究表明,CEA能增强非小细胞肺癌(NSCLC)的增殖和迁移,同时还能抑制顺铂诱导的NSCLC细胞凋亡。用 CEA 处理 A549 和 H1299 细胞会导致线粒体数量增加和脂滴积累。此外,我们的研究结果表明,CEA 在调节 NSCLC 细胞的脂肪酸代谢中发挥作用。抑制脂肪酸代谢可显著减少 CEA 介导的 NSCLC 细胞增殖和迁移。CEA通过激活PGC-1α信号通路影响NSCLC细胞的脂肪酸代谢和增殖。这一调节机制包括 CEA 增加细胞内 cAMP 水平,进而激活 PKA 并上调 PGC-1α。在 NSCLC 中,抑制 PKA-PGC-1α 信号通路可减少脂肪酸代谢以及 CEA 在体外和体内诱导的增殖和迁移。这些结果表明,CEA 通过调节脂肪酸代谢促进增殖和迁移。靶向CEA或PKA-PGC-1ɑ信号通路可能是治疗NSCLC的一种有前景的治疗方法。
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引用次数: 0
Effects of different treatments for type 2 diabetes mellitus on mortality of coronavirus disease from 2019 to 2021 in China: a multi-institutional retrospective study 2019年至2021年中国2型糖尿病不同治疗方法对冠状病毒病死亡率的影响:一项多机构回顾性研究
IF 4 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-17 DOI: 10.1186/s43556-024-00183-1
Ke Xu, Wu He, Bo Yu, Kaineng Zhong, Da Zhou, Dao Wen Wang
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引用次数: 0
Effects of different treatments for type 2 diabetes mellitus on mortality of coronavirus disease from 2019 to 2021 in China: a multi-institutional retrospective study. 2019年至2021年中国2型糖尿病不同治疗方法对冠状病毒病死亡率的影响:一项多机构回顾性研究。
IF 4 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-17 DOI: 10.1186/s43556-024-00183-1
Ke Xu, Wu He, Bo Yu, Kaineng Zhong, Da Zhou, Dao Wen Wang

The coronavirus disease (COVID-19) pandemic has continued for 5 years. Sporadic cases continue to occur in different locations. Type 2 diabetes mellitus (T2DM) is associated with a high risk of a poor prognosis in patients with COVID-19. Successful control of blood glucose levels can effectively decrease the risks of severe infections and mortality. However, the effects of different treatments were reported differently and even adversely. This retrospective study included 4,922 patients who have been diagnosed as COVID-19 and T2DM from 138 Hubei hospitals. The clinical characteristics and outcomes were compared and calculated their risk for death using multivariate Cox regression and Kaplan-Meier curves. After adjustment of age, sex, comorbidities, and in-hospital medications, metformin and alpha-glucosidase inhibitor (AGI) use performed lower all-cause mortality (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI]: 0.24-0.71; p = 0.001 for metformin; 0.53, 0.35-0.80, p = 0.002 for AGIs), while insulin use was associated with increased all-cause mortality (adjusted HR, 2.07, 95% CI, 1.61-2.67, p < 0.001). After propensity score-matched (PSM) analysis, adjusted HRs for insulin, metformin, and AGIs associated with all-cause mortality were 1.32 (95% CI, 1.03-1.81; p = 0.012), 0.48 (95% CI, 0.23-0.83, p = 0.014), and 0.59 (95% CI, 0.35-0.98, p = 0.05). Therefore, metformin and AGIs might be more suitable for patients with COVID-19 and T2DM while insulin might be used with caution.

冠状病毒病(COVID-19)大流行已持续 5 年。各地仍有零星病例发生。2 型糖尿病(T2DM)与 COVID-19 患者预后不良的高风险相关。成功控制血糖水平可有效降低严重感染和死亡的风险。然而,不同治疗方法的效果却不尽相同,甚至存在负面影响。这项回顾性研究纳入了湖北省138家医院的4922名被诊断为COVID-19和T2DM的患者。通过多变量 Cox 回归和 Kaplan-Meier 曲线比较了患者的临床特征和预后,并计算了他们的死亡风险。在对年龄、性别、合并症和院内用药进行调整后,使用二甲双胍和α-葡萄糖苷酶抑制剂(AGI)可降低全因死亡率(调整后的危险比[HR]为0.41;95%置信区间[CI]为0.24-0.71;P<0.05):二甲双胍为 0.24-0.71;P = 0.001;AGI 为 0.53、0.35-0.80,P = 0.002),而使用胰岛素则与全因死亡率升高有关(调整后的 HR 为 2.07,95% 置信区间 [CI]:1.61-2.67,P = 0.002)。
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引用次数: 0
Heterogeneity and molecular landscape of melanoma: implications for targeted therapy. 黑色素瘤的异质性和分子结构:对靶向治疗的影响。
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-10 DOI: 10.1186/s43556-024-00182-2
Yasaman Zohrab Beigi, Hossein Lanjanian, Reyhane Fayazi, Mahdieh Salimi, Behnaz Haji Molla Hoseyni, Mohammad Hafez Noroozizadeh, Ali Masoudi-Nejad

Uveal cancer (UM) offers a complex molecular landscape characterized by substantial heterogeneity, both on the genetic and epigenetic levels. This heterogeneity plays a critical position in shaping the behavior and response to therapy for this uncommon ocular malignancy. Targeted treatments with gene-specific therapeutic molecules may prove useful in overcoming radiation resistance, however, the diverse molecular makeups of UM call for a patient-specific approach in therapy procedures. We need to understand the intricate molecular landscape of UM to develop targeted treatments customized to each patient's specific genetic mutations. One of the promising approaches is using liquid biopsies, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), for detecting and monitoring the disease at the early stages. These non-invasive methods can help us identify the most effective treatment strategies for each patient. Single-cellular is a brand-new analysis platform that gives treasured insights into diagnosis, prognosis, and remedy. The incorporation of this data with known clinical and genomics information will give a better understanding of the complicated molecular mechanisms that UM diseases exploit. In this review, we focused on the heterogeneity and molecular panorama of UM, and to achieve this goal, the authors conducted an exhaustive literature evaluation spanning 1998 to 2023, using keywords like "uveal melanoma, "heterogeneity". "Targeted therapies"," "CTCs," and "single-cellular analysis".

葡萄膜癌(UM)的分子结构非常复杂,在遗传和表观遗传水平上都存在很大的异质性。这种异质性对这种不常见的眼部恶性肿瘤的行为和治疗反应起着至关重要的作用。使用基因特异性治疗分子进行靶向治疗可能有助于克服放射耐药性,但是,UM 的分子组成多种多样,因此在治疗过程中需要采用针对患者的方法。我们需要了解 UM 错综复杂的分子结构,以便针对每位患者的特定基因突变开发出针对性治疗方法。其中一种很有前景的方法是使用液体活检,如循环肿瘤细胞(CTC)和循环肿瘤 DNA(ctDNA),在早期阶段检测和监测疾病。这些非侵入性方法可以帮助我们为每位患者确定最有效的治疗策略。单细胞是一种全新的分析平台,能为诊断、预后和治疗提供宝贵的见解。将这些数据与已知的临床和基因组学信息相结合,可以更好地了解 UM 疾病所利用的复杂分子机制。在这篇综述中,我们重点关注 UM 的异质性和分子全景,为了实现这一目标,作者使用 "葡萄膜黑色素瘤"、"异质性"、"靶向治疗"、"免疫疗法"、"免疫治疗 "等关键词,对 1998 年至 2023 年的文献进行了详尽的评估。"靶向疗法"、"CTCs "和 "单细胞分析 "等关键词进行了详尽的文献评估。
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引用次数: 0
Construction of novel multi-epitope-based diagnostic biomarker HP16118P and its application in the differential diagnosis of Mycobacterium tuberculosis latent infection. 基于多表位的新型诊断生物标记 HP16118P 的构建及其在结核分枝杆菌潜伏感染鉴别诊断中的应用。
IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-29 DOI: 10.1186/s43556-024-00177-z
Jie Wang, Fan Jiang, Peng Cheng, Zhaoyang Ye, Linsheng Li, Ling Yang, Li Zhuang, Wenping Gong

Tuberculosis (TB) is an infectious disease that significantly threatens human health. However, the differential diagnosis of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) remains a challenge for clinicians in early detection and preventive intervention. In this study, we developed a novel biomarker named HP16118P, utilizing 16 helper T lymphocyte (HTL) epitopes, 11 cytotoxic T lymphocyte (CTL) epitopes, and 8 B cell epitopes identified from 15 antigens associated with LTBI-RD using the IEDB database. We analyzed the physicochemical properties, spatial structure, and immunological characteristics of HP16118P using various tools, which indicated that it is a hydrophilic and relatively stable alkaline protein. Furthermore, HP16118P exhibited good antigenicity and immunogenicity, while being non-toxic and non-allergenic, with the potential to induce immune responses. We observed that HP16118P can stimulate the production of high levels of IFN-γ+ T lymphocytes in individuals with ATB, LTBI, and health controls. IL-5 induced by HP16118P demonstrated potential in distinguishing LTBI individuals and ATB patients (p=0.0372, AUC=0.8214, 95% CI [0.5843 to 1.000]) with a sensitivity of 100% and specificity of 71.43%. Furthermore, we incorporated the GM-CSF, IL-23, IL-5, and MCP-3 induced by HP16118P into 15 machine learning algorithms to construct a model. It was found that the Quadratic discriminant analysis model exhibited the best diagnostic performance for discriminating between LTBI and ATB, with a sensitivity of 1.00, specificity of 0.86, and accuracy of 0.93. In summary, HP16118P has demonstrated strong antigenicity and immunogenicity, with the induction of GM-CSF, IL-23, IL-5, and MCP-3, suggesting their potential for the differential diagnosis of LTBI and ATB.

结核病(TB)是一种严重威胁人类健康的传染病。然而,如何鉴别诊断潜伏肺结核感染(LTBI)和活动性肺结核(ATB)仍然是临床医生早期检测和预防干预的难题。在这项研究中,我们利用 IEDB 数据库从与 LTBI-RD 相关的 15 个抗原中鉴定出的 16 个辅助性 T 淋巴细胞(HTL)表位、11 个细胞毒性 T 淋巴细胞(CTL)表位和 8 个 B 细胞表位,开发了一种名为 HP16118P 的新型生物标记物。我们利用各种工具分析了 HP16118P 的理化性质、空间结构和免疫学特征,结果表明它是一种亲水性和相对稳定的碱性蛋白。此外,HP16118P 表现出良好的抗原性和免疫原性,同时无毒、无过敏,具有诱导免疫反应的潜力。我们观察到,HP16118P 可刺激 ATB、LTBI 患者和健康对照组产生高水平的 IFN-γ+ T 淋巴细胞。HP16118P 诱导的 IL-5 有可能区分 LTBI 患者和 ATB 患者(p=0.0372,AUC=0.8214,95% CI [0.5843-1.000]),灵敏度为 100%,特异性为 71.43%。此外,我们还将 HP16118P 诱导的 GM-CSF、IL-23、IL-5 和 MCP-3 纳入 15 种机器学习算法以构建模型。结果发现,二次判别分析模型在区分 LTBI 和 ATB 方面表现出最佳诊断性能,灵敏度为 1.00,特异度为 0.86,准确度为 0.93。总之,HP16118P 具有很强的抗原性和免疫原性,能诱导 GM-CSF、IL-23、IL-5 和 MCP-3,这表明其具有鉴别诊断 LTBI 和 ATB 的潜力。
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Molecular biomedicine
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